Patient with statin-associated immune-mediated necrotizing myopathy presenting with subcutaneous edema, persistent bulbar weakness and absent anti-HMGCR.

Abstract

Dear Editor, Statin is commonly prescribed for treatment of dyslipidemia and prevention of cardiovascular disease. Musculoskeletal manifestations ranging from asymptomatic elevation of creatine kinase (CK), myalgia and muscle weakness, to life-threatening rhabdomyolysis, are well-described complications of statin use. More recently, statin has been recognized to be associated with immune-mediated necrotizing myopathy (IMNM).1, 2 We report here a patient with statin-associated IMNM who presented with atypical manifestations which included subcutaneous edema of the limbs and persistent bulbar weakness, despite spontaneous resolution of limb weakness and normalization of CK after cessation of statin, in addition to the absence of autoantibody against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR). To the best of our knowledge, these features have not been previously described. A 68-year-old man who had attended the dermatology out-patient clinic for pemphigus foliaceus complained of a 1-month history of muscle weakness associated with fatigue. Treatment of pemphigus in the past with high-dose prednisolone had shown good response and he was on prednisolone 5 mg daily as maintenance therapy. There was proximal muscle weakness and elevated CK of 10 215 U/L (normal range: < 170 U/L). Rhabdomyolysis was ruled out. He had dyslipidemia and had been on treatment with simvastatin for the past 7 years. Statin was promptly discontinued given the possibility of statin-induced myopathy. The patient refused further investigations. He presented 2 months later with increasing lethargy, progressive muscle weakness, dysphagia and swelling of both upper and lower limbs. Rheumatology consultation was sought. He admitted to choking on solid food; however, there was no slurred speech, diplopia, ptosis or breathlessness. There was no family history of muscle disease. He denied consumption of supplements or herbal remedies. Physical examination revealed brawny non-pitting edema over all extremities, which was more pronounced in the upper arms. Cutaneous signs of dermatomyositis were absent. Muscle power was assessed using the Medical Research Council (MRC) score: neck flexion was 5, shoulder abduction and adduction was 4 bilaterally, hip flexion and extension was 4 bilaterally, other muscle groups were 5. Examination of the other systems was essentially unremarkable. Investigation revealed CK of 9065 U/L. There was hypoalbuminemia at 26 g/L (normal: > 35 g/L) but no proteinuria. Erythrocyte sedimentation rate was 20 mm/h, C-reactive protein (CRP) was 131.5 mg/L (normal: < 5 mg/L) and hemoglobin was 10.1 g/dL. Renal function and thyroid function tests were normal. Hepatitis B, hepatitis C and human immunodeficiency virus serology were negative. Immunology was negative for antinuclear antibody, rheumatoid factor, anti-Jo-1 antibody and anti-signal recognition particle (anti-SRP) antibody. Tumor markers including prostate specific antigen, carcinoembryonic antigen, CA 19-9 and alpha-fetoprotein were within normal limits. Chest radiography and electrocardiography were unremarkable. Screening for internal malignancy, which comprised upper endoscopy, ENT (ear, nose and throat) examination and computed tomography (CT) of thorax, abdomen and pelvis did not reveal any evidence of malignancy. Biopsy of the left deltoid muscle was undertaken in order to arrive at a definitive diagnosis. In the interim period while waiting for the muscle biopsy report, muscle strength over his shoulder and pelvic girdles improved spontaneously to an MRC score of 5. This was accompanied by normalization of CK. Of note, his prednisolone dose had remained at 5 mg daily. Nonetheless, his dysphagia persisted. Endoscopic evaluation of swallowing revealed severe oropharyngeal dysphagia characterized by poor epiglottic deflection and poor pharyngeal contraction. Given the risk of aspiration, nasogastric feeding was recommended. Muscle biopsy report then showed features consistent with necrotizing myopathy. There were scattered necrotic and regenerating fibres with sparse inflammatory cell infiltrate (Fig. 1). In addition, sarcolemmal up-regulation of major histocompatibility complex class 1 (MHC-1) was demonstrated in normal and necrotic muscle fibres (Fig. 2). No evidence of metabolic myopathy was noted. Given the history, clinical examination and investigations, statin-associated IMNM was strongly suspected. To further support this diagnosis, his serum was sent for detection of anti-HMGCR autoantibodies. However, the result was negative. Oral prednisolone was started at 60 mg daily in conjunction with azathioprine. Our patient attempted oral intake 2 weeks later and was able to swallow without choking. By 4 weeks, the subcutaneous edema over his limbs had resolved. At 6 weeks, he had formal re-assessment of swallowing which revealed complete resolution of bulbar weakness. Over the ensuing months, his muscle strength and CK continued to remain normal, which permitted tapering of prednisolone. Meanwhile azathioprine was optimized to 2 mg/kg/day. The key features in statin-associated IMNM include proximal muscle weakness, an elevated CK that develops during statin therapy and that persists despite cessation of statin,1, 2 a muscle biopsy showing muscle necrosis with scanty inflammation, up-regulation of MHC-I expression in non-necrotic muscle fibres1 and improvement with immunosuppressive therapy. These characteristics were well demonstrated in our patient. Paucity of inflammation in muscle biopsy clearly distinguishes IMNM from inflammatory myopathies, in particular, polymyositis and dermatomyositis. The prevalence of statin-associated IMNM is unknown and is believed to be a rare entity. In addition, the mechanism by which statin causes IMNM remains unclear. Nevertheless, it is important for rheumatologists with referred cases of myopathy to be aware of and identify this condition. Our patient demonstrated three interesting phenomena: presence of subcutaneous limb edema, persistent bulbar weakness despite spontaneous resolution of limb weakness and normalization of CK after cessation of statin, in addition to the absence of anti-HMGCR antibody. Subcutaneous edema has been described as a presenting symptom in patients with inflammatory myositis, albeit rarely.3, 4 To date there has been no report describing subcutaneous edema in statin-associated IMNM, and this may well be the first reported case. The pathogenesis of subcutaneous edema in myopathy remains unknown. It may have a close link to the pathophysiology of IMNM because, as illustrated in our patient, it resolved after high-dose corticosteroids. It was noteworthy that, in spite of clear demonstration of necrotizing myopathy on muscle biopsy, our patient was able to achieve spontaneous improvement of muscle strength in the limbs with normalization of CK following cessation of statin. Nonetheless, there was a lack of improvement in the bulbar weakness, which only showed a dramatic response after immunosuppressive therapy. This indicates that spontaneous recovery in the limbs can sometimes occur but resolution of bulbar weakness would require immunosuppressive therapy. The latter may well be a unique feature of smooth muscle. Dissimilar behaviour of various muscle types, that is, skeletal muscle (limbs) and smooth muscle (bulbar), is perhaps not unexpected. Even though anti-HMGCR has been shown to be highly specific for patients with IMNM,5-7 and its frequency is higher in those who had used statin, anti-HMGCR was not detected in our patient. In spite of this, we are still confident that our patient indeed had statin-associated IMNM because of the following reasons. Statin use was clear in the history. In addition, prompt response of bulbar weakness to immunosuppressive therapy in conjunction with the presence of class I MHC on the sarcolemma of non-necrotic muscle fibers underscores an immune-mediated mechanism. Thus, we can hypothesize that anti-HMGCR may not always be detected in patients with statin-associated IMNM, and the absence of anti-HMGCR does not preclude this diagnosis in patients who demonstrate typical clinical presentations of this condition. Statin-associated IMNM is considered as one of several immune-mediated myopathies which, among others, include polymyositis, dermatomyositis and inclusion body myositis. Diagnosis is established upon recognition of its distinctive features which include a history of statin exposure, elevated CK levels, persistence of active myopathy despite cessation of statins and the requirement of immunosuppressive therapy for resolution of myopathy, histological findings of muscle fiber necrosis with absence of significant inflammation and up-regulation of MHC-1 expression in necrotic as well as non-necrotic muscle fibers, and presence of anti-HMGCR.8 The etiology of statin-associated IMNM and the exact mechanism of how statins induce myopathy are still poorly understood. HMGCR is a rate-limiting enzyme in cholesterol synthesis, and statins competitively inhibit HMGCR. An autoimmune basis for statin-associated IMNM was established with the detection of anti-HMGCR, which was found to be quite specific for IMNM.5 This suggested that statins were capable of triggering the immune response, resulting in immune-mediated myopathy, as well as sustaining the immune response despite cessation of statins.6 Patients suspected of statin-associated IMNM should discontinue statins immediately. Immunosuppressive therapy is generally required, with high-dose corticosteroids being the initial treatment. Other immunosuppressive agents that have been described include methotrexate, azathioprine, rituximab, cyclophosphamide and cyclosporine. Intravenous immunoglobulin and plasmapheresis are additional modes of therapy.9, 10 The authors thank Dr Andrew Woods of Churchill Hospital, Oxford University Hospitals NHS Foundation Trust (http://www.ouh.nhs.uk/immunology) and Chelsea Bentow from Inova Diagnostics for providing assay support to test for anti-HMGCR antibodies; Professor Khean Jin Goh and Tomica Ambang of Universiti Malaya for their help in testing for anti-SRP antibodies.